The invention relates to inhibitors of neutral endopeptidase enzyme (NEP), uses thereof, processes for the preparation thereof, intermediates used in the preparation thereof and compositions containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas including the treatment of male and female sexual dysfunction, particularly female sexual dysfunction (FSD), especially wherein the FSD is female sexual arousal disorder (FSAD).
NEP inhibitors are disclosed in WO 91/07386 and WO 91/10644.
The use of NEP inhibitors for treating FSD is disclosed in EP1 097 719-A1.
According to a first aspect, the invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof; 
wherein
R1 is C1-6alkyl which may be substituted by one or more substituents, which may be the same or different, selected from the list: halo, hydroxy, C1-6alkoxy, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, carbocyclyl (preferably C3-7cycloalkyl, C3-7cycloalkenyl or phenyl), carbocyclyloxy (preferably phenoxy), C1-4alkoxycarbocyclyloxy (preferably C1-4alkoxyphenoxy), heterocyclyl, heterocyclyloxy, xe2x80x94NR2R3, xe2x80x94NR4COR5, xe2x80x94NR4SO2R5, xe2x80x94CONR2R3, xe2x80x94S(O)pR6, xe2x80x94COR7 and xe2x80x94CO2(C1-4alkyl); or R1 is carbocyclyl (preferably C3-7cycloalkyl or phenyl) or heterocyclyl, each of which may be substituted by one or more substituents from said list, which substituents may be the same or different, which list further includes C1-6alkyl; or R1 is hydrogen, C1-6alkoxy, xe2x80x94NR2 R3 or xe2x80x94NR4SO2R5;
wherein
R2 and R3, which may be the same or different, are carbocyclyl (preferably C3-7cycloalkyl or phenyl) or heterocyclyl (each of which may be substituted by C1-4alkyl, hydroxy or C1-4alkoxy); or are hydrogen or C1 4alkyl; or R2 and R3 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C1-4alkyl)piperazinyl group;
R4 is hydrogen or C1-4alkyl;
R5 is C1-4alkyl, CF3, carbocyclyl (preferably phenyl), C1-4alkylcarbocyclyl (preferably C1-4 alkylphenyl), C1-4alkoxycarbocyclyl (preferably C1-4alkoxyphenyl), heterocyclyl, C1-4alkoxy or xe2x80x94NR2R3;
R6 is C1-4alkyl, carbocyclyl (preferably phenyl), heterocyclyl or NR2R3; and
R7 is C1-4alkyl, carbocyclyl (preferably C3-7cycloalkyl or phenyl) or heterocyclyl;
p is 0, 1, 2 or 3;
X is the linkage xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)qxe2x80x94Oxe2x80x94 (wherein Y is attached to the oxygen); wherein one or more hydrogen atoms in linkage X may be replaced independently by C1-4alkoxy; hydroxy; hydroxyC1-3alkyl; C3-7cycloalkyl; carbocyclyl; heterocyclyl; or by C1-4alkyl optionally substituted by one or more fluoro or phenyl groups; n is 3, 4, 5, 6 or 7; and q is 2, 3, 4, 5 or 6; and
Y is phenyl or pyridyl, each of which may be substituted by one or more groups R8 which may be the same or different, wherein R8 is hydroxy; mercapto; halogen; cyano; acyl; amino; mono(C1-4alkyl)amino; di(C1-4alkyl)amino; carbocyclyl or heterocyclyl (either of which is optionally substituted by C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C16alkylthio or halogen); C16alkoxy; phenoxy; C1-6alkylthio; phenylthio; or alkyl optionally substituted by C1-6alkoxy, haloC1-6alkoxy, C1-6alkylthio, halogen or phenyl; or
two R8 groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused 5- or 6-membered carbocyclic or heterocyclyic ring, optionally substituted by C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C1-6alkylthio or halogen.
Preferably R1 is hydrogen, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-3alkyl, C1-6alkoxyC1-6alkoxyC1-3alkyl or C1-6alkyl substituted by phenyl.
More preferably R1 is hydrogen, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-3alkyl (preferably methoxyC1-3alkyl) or C1-6alkoxyC1-6alkoxyC1-3alkyl (preferably methoxyethoxymethyl).
More preferably still R1 is C1-4alkyl (preferably propyl) or C1-6alkoxyC1-3alkyl (preferably methoxyC1-3alkyl, more preferably methoxyethyl).
A preferred group of compounds are of formula Ia: 
Preferably n is 3 or 4, more preferably 3.
Preferably q is 2 or 3, more preferably 2.
Preferably X is xe2x80x94(CH2)nxe2x80x94 wherein one or more hydrogen atoms in linkage X may be replaced by one or more of the groups defined for X in the first aspect.
Preferably R8 is C1-6alkyl, C1-6alkoxy, hydroxy, mercapto, halo, cyano, carbocyclyl or heterocyclyl; or two R8 groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused 5- or 6-membered carbocyclic or heterocyclyic ring, optionally substituted by C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C1-6alkylthio or halogen.
When R8 is carbocyclyl, preferred groups are cyclopentyl, cyclopropyl, cyclohexyl or phenyl.
When R8 is heterocyclyl, preferred groups are pyridyl, oxadiazolyl, pyrazolyl or triazolyl.
When Y is phenyl and two R8 groups on adjacent carbon atoms together with the interconnecting carbon atoms form a fused 5- or 6-membered carbocyclic or heterocyclyic ring, preferred fused ring systems are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothiazolyl.
Preferred compounds of the invention are:
(2R)-2-{[1-({[3-(4-methoxyphenyl)propyl]amino}carbonyl)cyclopentyl]methyl}pentanoic acid (Example 16),
3-{[1-({[3-(4-methoxyphenyl)propyl]amino}carbonyl)cyclopentyl]propanoic acid (Example 18),
3-{[1-({[3-(2,3-dihydro-1-benzofuran-5-yl)propyl]amino}carbonyl)cyclopentyl]propanoic acid (Example 21),
2-{[1-({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (Example 15),
2-{[1-({[3-(4-fluorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (Example 4),
4-methoxy-2-{[1-({[3-(4-methoxyphenyl)propyl]amino}carbonyl)cyclopentyl]-methyl}butanoic acid (Example 1),
2-{[1-({[3-(2,3-dihydro-1-benzofuran-5-yl)propyl]amino}carbonyl)cyclopentyl]-methyl}-4-methoxybutanoic acid (Example 11),
(2S)-2-{[1-({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (Example 22), and
(2S)-2-{[1-({[3-(2,3-dihydro-1-benzofuran-5-yl)propyl]amino}carbonyl)cyclopentyl]-methyl}-4-methoxybutanoic acid (Example 25).
A particularly preferred compound is (2S)-2-{[1-({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (Example 22).
Unless otherwise indicated, any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
Unless otherwise indicated, any carbocyclyl group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl groups contain up to 3 double bonds. A preferred aromatic carbocyclyl group is phenyl. The term carbocylic should be similarly construed. In addition, the term carbocyclyl includes any fused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.
Unless otherwise indicated, any heterocyclyl group contains 5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl. In addition, the term heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl. The term heterocyclic should be similarly construed.
Halo means fluoro, chloro, bromo or iodo.
For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternatives groups, the selected groups may be the same or different.
For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
The pharmaceutically or veterinarily acceptable salts of the compounds of formula I which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids. Examples include the HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. Compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chloine, megulamine and diethanolamine salts. For reviews on suitable pharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.
Hereinafter, the compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, defined in any aspect of the invention or preferred embodiment (except intermediate compounds in chemical processes) are referred to as xe2x80x9ccompounds of the inventionxe2x80x9d.
The pharmaceutically acceptable solvates of the compounds of the invention include hydrates thereof.
The compounds of the invention and intermediates may possess one or more chiral centres and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention.
Individual enantiomers may be obtained by a variety of techniques known to the skilled chemist, such as by high pressure liquid chromatography (HPLC) of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active base, as appropriate. A preferred optically active base is pseudoephedrine (see Preparation 69).
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C.
The compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included within the scope of the present invention.
For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, xcex1-pyridonyl.